Biology subjects

Xiao, F.

Publications and source records attributed to Xiao, F..

At least 19 recordsLinked to original sources

bioRxiv2026

Glioblastoma Hijacks Astrocyte Ribosomes to Feul Malignancy through Translatome Reprogramming

Cancer cells demand elevated protein synthesis, yet whether they directly requisition ribosomes from microenvironmental host cells remains unknown. Here, utilizing in vivo and in vitro ribosome tracing, we show that glioblastoma (GBM) cells hijack ribosomes from surrounding astrocytes via tunneling nanotube-like structures. This transfer supports GBM malignancy in both murine and patient derived models. Single cell RNA sequencing along with whole cell and cell source traceable ribosome profiling reveal that transferred ribosomes are translationally active and selectively reprogram the tumor translatome, prioritizing cell-cycle genes and driving interferon-response-mediated immune evasion. Through a genome wide CRISPR screen, we identify INTS12 as a critical mediator of ribosome transfer. Genetic inactivation or AAV-mediated knockdown of INTS12 impairs ribosome uptake, curbs translation and proliferation, remodels the immunosuppressive landscape, and extends survival in orthotopic models. Our study uncovers a parasitic translation-support mechanism in GBM, establishing INTS12 as a therapeutic vulnerability to disrupt ribosome transfer.

cancer biology↗

bioRxiv2026

Histological morphometric correlates of MRI-defined cortical thinning in temporal lobe epilepsy

Large-scale MRI studies have consistently demonstrated progressive and age-accelerated neocortical thinning in temporal lobe epilepsy (TLE). These findings are frequently interpreted as evidence of cumulative neurodegeneration. However, the histopathological substrates underlying MRI-confirmed cortical thinning in epilepsy remain poorly defined. In particular, it is unknown whether cortical thinning reflects irreversible neuronal loss or potentially reversible epilepsy-related network alterations in cortical microstructure. We analysed the resected middle temporal gyrus from 117 individuals undergoing surgery for temporal lobe epilepsy, including cases with (n= 74) or without hippocampal sclerosis (HS) and 12 cases with additional temporal lobe sclerosis (TLS, or Focal Cortical Dysplasia IIIa), defined by a distinct pattern of cytoarchitectural reorganisation and gliosis involving superficial layers. All cases were stratified by the presence or absence of pre-operative MRI-defined cortical thinning of the middle temporal gyrus, quantified using CAT12 relative to healthy controls. On NeuN-immuno-labelled sections using automated image analysis we assessed neuronal spatial distributions relative to their size and packing density; relative cortical layer thickness and sulcal-gyral cytoarchitectural variation were also quantified. MRI-defined cortical thinning was not associated with diffuse neuronal loss. Instead, thinning correlated with increased neuronal density and altered cell-size spatial organisation in superficial and deep layers, particularly in right temporal lobe epilepsy cases with HS. There was limited evidence of layer-specific laminar thinning, being confined to layer VI in the right TLE/HS group only. Of note, TLS cases did not show either cortical thinning on MRI or laminar thinning on histology compared to cases without TLS but altered neuronal densities and composition that was not confined to the superficial cortex. MRI cortical thinning was also characterised by attenuation of normal sulcal/gyral cytoarchitectural variations suggesting disruption of cortical architectural gradients. In contrast, cases with HS but without MRI cortical thinning demonstrated loss of the expected inter-hemispheric cytoarchitectural asymmetry, indicating a distinct pathological process dissociated from thinning. Clinical-pathological correlations were lateralised, including age of onset, further supporting distinct mechanisms contributing to MRI cortical thinning between left and right TLE. These findings challenge the prevailing assumption that MRI-defined cortical thinning in epilepsy reflects progressive neuronal degeneration. Rather than laminar neuronal loss and atrophy, thinning was associated with altered neuronal packing and cell-size distributions between layers. This points towards altered neuropil volumes, including myelin content and dendritic remodelling, in turn suggesting potentially reversible dynamic seizure- or network-related processes.

pathology↗

bioRxiv2026

Flux-species sampling enables holistic exploration of biocircuit behavior

Biocircuit behavior is usually discovered by drawing uncertain kinetic parameters and simulating, but the scored phenotypes are functions of steady-state species, catalytic fluxes, dominance relations, and local response matrices. We introduce flux-species sampling (FSS), which samples that functional layer directly and algebraically inverts to parameters. This coordinate change turns regulatory modes into simple dominance chambers, gives every full-dimensional behavior-realizing regime positive measure, and can replace the sampling stage of existing pipelines without changing downstream stability or phenotype tests. A sequestration toy shows how a large species regime can collapse into a narrow parameter strip. In an enzymatic feedback motif, FSS rescues free-A* adaptation missed by parameter sampling and identifies the regime as non-Michaelian and complex-dominated. In MultiFate-N, FSS separates a sampling limitation from a structural limitation and rescues parameter sets realizing all 2N states. HighlightsO_LIFlux-species sampling (FSS) draws the control/function layer where biocircuit behavior is read C_LIO_LIFSS boxes intersect every full-dimensional behavior-realizing regime with positive measure C_LIO_LIFSS is no slower than parameter-space sampling and is a hot fix for existing pipelines C_LIO_LIFSS rescues non-Michaelian free-A* adaptation missed by parameter sampling C_LIO_LIFSS rescues the all-2N symmetric MultiFate regime missed by fixed parameter boxes C_LI eTOC blurbThis study reframes biocircuit exploration by sampling steady-state species and fluxes rather than raw parameters. The resulting flux-species coordinate exposes regulatory dominance regimes, rescues adaptation and multistability regimes missed by parameter sampling, and gives finite sampling nulls an explicit scope.

systems biology↗

bioRxiv2026

LARP4 is a B cell-specific metabolic checkpoint for plasma cell differentiation and a therapeutic target in systemic lupus erythematosus

RNA-binding protein LARP4 plays an important role in T cell activation and differentiation, but its role in B cell biology and the pathogenesis of systemic lupus erythematosus (SLE) remains unclear. This study found that LARP4 was specifically highly expressed in B cells of SLE patients and was positively correlated with disease activity. By constructing T cell-specific and B cell-specific conditional knockout mice, we found that deletion of LARP4 in B cells, but not in T cells, significantly alleviated pristane-induced and Bm12-induced lupus nephritis. Further analysis showed that LARP4 deletion selectively inhibited B cell differentiation into plasma cells, but did not affect germinal center B cell formation. Integrated transcriptomic and metabolomics analyses revealed that this effect is due to reduced phosphatidic acid synthesis and decreased mTORC1 activity caused by mitochondrial oxidative phosphorylation dysfunction. Furthermore, we used LIPEP, a LARP4 inhibitory peptide that effectively mimicked the therapeutic effects of LARP4 gene knockout in the MRL/lpr spontaneous lupus model and outperformed cyclophosphamide in reducing glomerular immune complex deposition and improving extrarenal dermatitis. These results indicates that LARP4 is a key metabolic checkpoint regulating B cell differentiation into Plasma cells and suggest that it may be a potential therapeutic target for SLE.

immunology↗

bioRxiv2026

MintCNA: A Unified Framework for Integrative Copy Number Profiling with Single-Cell Multi-Omics Data

Chromosomal copy number alterations (CNAs) are key drivers of tumor evolution, disease progression and therapeutic resistance, and the identification of them is an important step to delineate tumor clonal structure. However, accurately resolving CNA landscapes from single-cell data remains challenging. Most existing tools analyze one omics layer at a time and are susceptible to assay-specific noises, limiting their ability to recover shared or modality-specific CNAs. Recent single-cell multi-omics techniques enable joint sequencing of multiple molecular layers in the same cells, yet in silico methods that fully exploit such complementary multi-modal data for CNA analysis are still missing. Here we present a single-cell multi-omics integration framework, MintCNA, a unified framework for CNA detection from paired multi-omics data. MintCNA integrates traditional statistical modeling with embedded deep learning structure to enhance CNA profiling across multi-omics. We use an attention-guided convolutional autoencoder for data denoising and perform multivariate change-point detection utilizing a sliding-window screening and ranking procedure. Missingness-adjusted CUSUM statistics are constructed which jointly aggregate omics features by a data-adaptive projection to detect genome-wide chromosomal breakpoints. Across various simulations and applications to a colorectal cancer multi-omics dataset, MintCNA consistently outperforms existing single-omics CNA callers in detection accuracy. MintCNA provides a single-cell CNA tool that integrates paired scDNA-seq and scRNA-seq, supporting the study of intra-tumor heterogeneity and tumor evolution.

bioinformatics↗

bioRxiv2026

CN-RNN: a Deep Learning Framework for Copy Number Variation Detection with Exome Sequencing Data

Copy number variations (CNVs) are major structural genomic variants that contribute to a wide range of human diseases. Accurate detection of CNVs from whole-exome sequencing (WES) data has been a long-sought goal for clinical and population genetic studies. Despite recent progress, existing WES-based CNV callers still suffer from high false-positive rates and reduced recall for short-length variants, and current deep learning methods have not fully used complementary information in region-level genomic features. Here we present CN-RNN, a deep learning-based CNV caller for WES data. The model combines a bidirectional long short-term memory (BiLSTM) branch that captures local depth changes and contextual dependencies across neighboring exons with a parallel multi-layer perceptron (MLP) branch that encodes region-level metadata such as GC content, mappability, and exon length. CN-RNN was trained on the Autism Sequencing Consortium (ASC) parent-child trio cohort using the Mendelian rule of inheritance to ensure high-quality training sets. It was evaluated across three independent datasets, in which we showed that CN-RNN outperformed existing WES-based CNV callers and deep learning methods. CN-RNN offers a scalable, accurate tool for CNV profiling in WES-based studies and supports broader application of CNV analysis in population and clinical research. CN-RNN is available at https://github.com/FeifeiXiao-lab/CN-RNN.

genetics↗

bioRxiv2026

Robust Inference of Individualized Treatment Effect in Mendelian Randomization

Mendelian randomization (MR), leveraging genetic variants as instrumental variables (IVs), is widely used to draw causal conclusions in the presence of unmeasured confounding, but most MR analyses focus on average treatment effects and rely on strong assumptions. For precision medicine, the primary target is instead the individualized treatment effect (ITE); yet in MR, such effects are not point-identified under core IV assumptions, and valid inference for identifiable bounds of the ITEs is particularly challenging. In this work, we propose a robust partial identification inference framework for the identifiable bounds of the ITEs under MR allowing multiple IVs. Under minimal causal assumptions, we derive a sharp inference procedure for the bounds of ITE by adopting a multiplier bootstrap procedure with data-adaptive bootstrap distribution shifting and heterogeneous variance adjustment. In theory, we prove that the proposed method achieves nominal coverage and asymptotic sharpness. Further, we extend the procedure to tolerate possible invalid IVs under a minimal proportion rule assumption by aggregating over plausible IV subsets while preserving coverage. Simulation studies demonstrate that the proposed methods attain nominal coverage and substantially shorter intervals than existing procedures. We illustrate the framework using data from the Alzheimers Disease Neuroimaging Initiative to assess heterogeneous causal effects of TREM2 expression on Alzheimers disease risk across education-defined subgroups.

genetics↗

bioRxiv2026

Structural basis of MK-97 positive allosteric modulation at the M4 mAChR

Positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor (mAChR) represent a promising therapeutic strategy for treating cognitive deficits and neuropsychiatric disorders. While first-generation M4 mAChR PAMs, like LY2033298, demonstrated proof-of-concept, second-generation compounds, such as MK-97, exhibit substantially improved potency and reduced species variability. Here we report the cryo-EM structure of the M4 mAChR bound to the endogenous agonist, acetylcholine, and MK-97 at 2.7 [A] resolution, revealing the molecular basis for improved M4 mAChR PAM activity. MK-97 adopts a distinctive boomerang-shaped conformation within the extracellular-facing allosteric binding site, with a central pyridine vertex, a lower cyclopentylmethylpyrazole arm extending toward the floor of the orthosteric site, and an upper isoindolinone arm projecting toward extracellular loop 2 (ECL2). This extended binding mode establishes a distributed interaction network across transmembrane helices TM2, TM3, TM5, TM6, and TM7, with key contacts including a hydrogen bond with Y922.64 and a {pi}-{pi} stacking interaction with W4357.35. Integration of structural data, molecular dynamics simulations, and mutagenesis validation reveals that the high affinity of MK-97 derives from optimized engagement across all three binding regions rather than dependence on any single critical contact. Insights from comprehensive structure-activity relationship (SAR) studies provide a molecular framework for the rational design of next-generation M4 mAChR PAMs with improved pharmacological properties. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=70 SRC="FIGDIR/small/723386v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@75cb90org.highwire.dtl.DTLVardef@1876c9corg.highwire.dtl.DTLVardef@1eba8d0org.highwire.dtl.DTLVardef@9818ad_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2026

Sleeve gastrectomy improves metabolic health, cognition, and Alzheimer's Disease pathology in 3xTG mice

Obesity and diabetes are well-established risk factors for Alzheimers disease (AD), implicating metabolic dysfunction in AD pathogenesis. Sleeve gastrectomy (SG) is among the most effective metabolic interventions available, yet its impact on AD progression remains poorly understood. We hypothesized that SG performed early in life would improve metabolic health, attenuate AD pathology, and preserve cognition in a transgenic AD mouse model. Five-week-old female 3xTg-AD mice were preconditioned on a Western diet (WD) to induce obesity and glucose intolerance, then randomized to SG or sham surgery and maintained on either standard chow or continued WD for 12 months. Metabolic phenotyping, body composition, and cognitive assessments (Novel Object Recognition, Barnes Maze, Fear Conditioning) were performed longitudinally, with histological and molecular analysis of brain tissue at endpoint. Under chow-fed conditions, SG reduced adiposity, improved insulin sensitivity, and decreased cortical A{beta} plaque burden, accompanied by attenuated gliosis (GFAP, IBA1) and region-specific, insulin pathway-dependent modulation of autophagy. Under persistent WD, SG improved metabolic health, frailty, spatial cognition, and A{beta} pathology, again with corresponding perturbations in autophagy pathway activity. Across all groups, food intake did not differ significantly, indicating that these effects were not secondary to caloric restriction. Collectively, these data suggest that SG engages neuroprotective brain insulin signaling pathways, supporting metabolic surgery as a promising disease-modifying intervention for AD prevention in individuals with obesity.

neuroscience↗

bioRxiv2026

Integrative Transcriptomic and Functional Analysis Reveals Fatty Acyl Elongases Involved in Sex Pheromone Biosynthesis in Rice Leaffolder, Cnaphalocrocis medinalis (Lepidoptera: Pyraloidea)

Elongases are essential enzymes in the biosynthesis of sex pheromones in many lepidopteran species. Together with desaturases, they determine the carbon skeletons of many pheromone precursors, thereby contributing to the production of species-specific chemical signals. However, to date, such fatty acyl elongase gene has not been functionally characterized. The rice leaffolder, Cnaphalocrocis medinalis, utilizes a blend of C18 monounsaturated aldehydes and alcohols as its sex pheromone, implying a critical elongation step from C16 precursors. In this study, we performed pheromone gland transcriptome analysis and identified 45 candidate biosynthetic genes. Functional assays in Nicotiana benthamiana showed that the {Delta}11 desaturase Cmed070400 produces (Z)-11-hexadecenoic acid, which serves as the substrate for elongation. Multiple elongases catalyzed its conversion to (Z)-13-octadecenoic acid, with Cmed092440 showing the highest activity. These findings provide the first experimental evidence for elongase-mediated formation of C18 pheromone precursors in C. medinalis. The identification of a minimal set of functionally active enzymes further enables reconstruction of this pathway in plant systems, offering a basis for sustainable production of pheromone precursors for pest management applications.

zoology↗

bioRxiv2026

The tongue-brain axis mediates a hidden amino acid appetite

Selecting a diet containing all essential amino acids (EAAs) is critical for health. Following EAA deprivation, animals can select a nutritiously complete food source; however, the underlying mechanisms in vertebrates remain unclear. In mice, we show that leucine deficiency activates hypothalamic agouti-related protein (AgRP) neurons, which project to the paraventricular thalamus (PVT) via {gamma}-aminobutyric acid and are required for EAA deficiency-induced leucine appetite in mice. Furthermore, the peripheral tongue amino acid sensor general control nonderepressive-2 (GCN2) mediates acute EAA appetite via AgRP neurons. Together, these findings identify a tongue-AgRP-PVT circuit underlying EAA appetite, which is important for the rapid and accurate selection of essential nutrients.

neuroscience↗

bioRxiv2026

Female resistance to the metabolic benefits of protein restriction is reversed by ovariectomy in mice

Dietary protein intake mediates healthy aging in diverse species, with consumption of a low protein (LP) diet improving metabolic health in both humans and mice. In mice, the benefits of LP diets are sex-specific, with males exhibiting a stronger response to a LP diet than females. The reason for this sexually dimorphic response is unknown, but we hypothesized that sex hormones might be responsible for this difference. Here, we tested the role of sex hormones in the response to a LP diet by feeding intact and gonadectomized mice of both sexes either a Control (21% of calorie from protein) or LP (7% of calories from protein) diet, and assessing the effects on weight, body composition, glycemic control, and energy balance over the course of three months, followed by molecular and histological analysis of tissues from each group. We confirm that males show a stronger metabolic response to an LP diet than females, but that ovariectomy sensitizes female mice to the metabolic effects of an LP diet, making them respond more similarly to males; conversely, castration does not substantially impact the response of males to an LP diet. Molecularly, we find that gonadectomy and sex are important interactors that mediate the response of mechanistic target of rapamycin (mTOR) signaling, lipid homeostasis, and thermogenesis to an LP diet. Together, this data shows that the resistance of female mice to an LP diet is mediated by ovarian hormones and suggests the possibility that older female humans might receive enhanced benefits from LP diet feeding.

physiology↗

bioRxiv2026

Effects of lumbar disc injury and nociception on trunk motor control during rat locomotion

Intervertebral disc (IVD) injury is a major cause of low-back pain and can lead to structural deficits and mechanical instability. When the IVD is compromised, neuromuscular compensation by paraspinal muscles, such as the multifidus (MF) and longissimus (ML), is critical for maintaining spine stability. However, it is unknown how IVD injury and its interaction with nociception affect neuromuscular control. This study assessed the effects of IVD injury and additional muscle-derived nociception on trunk motor control during locomotion in a rat model. IVD injury was induced via needle puncture at L4/L5. One week later, hypertonic saline was injected into the lumbar MF to induce nociception. Trunk and pelvic kinematics, bilateral EMG activity of MF and ML were recorded during treadmill locomotion at baseline, one week after IVD injury, and immediately following hypertonic saline injection. Trunk and pelvic kinematics and bilateral muscle activation patterns remained largely consistent across conditions. No significant changes were found in stride duration, pelvic, lumbar and spine angle changes, variability, or movement asymmetry. MF activation was bilaterally synchronized, whereas ML showed left-right alternating activation patterns. Following IVD injury, right MF mean activation and EMG variability increased significantly compared to baseline. When muscle-derived nociception was added in the unstable spine (IVD injury) condition, left MF minimum amplitude was significantly reduced, and instability-related increases in right MF mean activation and variability were attenuated, but not fully reversed. These findings suggest that IVD injury, alone or in combination with muscle-derived nociception, elicits localized neuromuscular adaptations without disrupting the global locomotor patterns.

neuroscience↗

bioRxiv2026

Mechanical and morphological effects of intervertebral disc injury: a systematic review of in vivo animal studies

Intervertebral disc degeneration (IVDD) compromises disc structures and mechanics, yet systematic evaluations of the mechanical responses and their relationship to morphological changes in preclinical models remain limited. This systematic review and meta-analysis synthesized mechanical and morphological alterations following experimental disc injury in in vivo animal models. Searches of MEDLINE, EMBASE and Web of Science databases were conducted in accordance with PRISMA guidelines. Study quality and risk of bias were assessed using modified CAMARADES and SYRCLE tools. Twenty-eight studies were included. Pooled analyses showed significant reductions in stiffness, Youngs modulus, and disc height, and significant increases in range of motion and degeneration grade, indicating both mechanical and structural deterioration. Youngs modulus appeared to be the most sensitive marker of functional degeneration. By contrast, creep and other viscoelastic responses showed non-significant changes. High heterogeneity was evident across studies, reflecting variability in injury models, species, timepoints, and testing methods. Evidence of publication bias was detected in several domains, and moderate methodological quality was noted with overall insufficient blinding and lack of sample size calculations. In vivo animal models of IVDD demonstrate robust and consistent mechanical and morphological degeneration after injury. Youngs modulus is a sensitive mechanical indicator, supporting its use in future preclinical research. Standardization of outcome definitions, methodology, and reporting is essential to improve comparability and enhance translation of preclinical findings to clinical research.

bioengineering↗

bioRxiv2026

Divergent chromatin remodeling trajectories in CD66b⁺ MDSCs distinguishes recovery from chronic critical illness after sepsis

Sepsis survivors exhibit divergent clinical trajectories, including rapid recovery (RAP) or progression to chronic critical illness (CCI), yet how these outcomes are linked to epigenetic repression remains poorly defined. Here, we applied an optimized Omni-ATAC approach to profile chromatin accessibility in CD66b myeloid-derived suppressor cells (MDSCs) from healthy participants and longitudinally sampled sepsis cohorts stratified by outcome. RAP samples progressively restored healthy chromatin states, whereas CCI samples remained epigenetically fixed in aberrant configurations. Chromatin remodeling exhibited strong pathway specificity: promoters associated with MHC class II antigen presentation were coordinately repressed in CCI, while MHC class I antigen processing and presentation machinery remained preserved. Genome-wide analyses revealed extensive promoter remodeling during recovery in RAP, including immune regulatory loci such as ARG1, CD274, and S100A8/A9, contrasted with broad suppression of immune, metabolic, and chromatin regulatory programs in CCI. These findings define divergent epigenetic trajectories in post-sepsis MDSCs and implicate selective failure of antigen presentation as a mechanism of sepsis-induced immunoparalysis in CCI.

immunology↗

bioRxiv2026

Evaluating valid parameter regimes for biocircuits

Biocircuit functions are often valid only in specific parameter regimes, yet these regimes are rarely made explicit. We use a holistic analysis method based on regimes to derive validity conditions and introduce the Realizability Index (R-index), quantifying the size of the valid regions in log-parameter space. The framework is applied to Michaelis-Menten kinetics, Hill functions, and enzymatic negative-feedback adaptation, showing how circuit structure and experimental control variables shape functional realizability. Our analysis shows the Hill functions R-index goes to zero in sequential binding with increasing Hill coefficient. We also resolve an active debate about whether negative-feedback adaptation is realizable when competitive binding is taken into account, and demonstrates the superiority of the holistic R-index method over numerical parameter scans that lead to incorrect conclusions. R-index defines a validity-aware language for studying and designing functional biocircuits.

synthetic biology↗

bioRxiv2025

Prolonged Loss of Oxidative Phosphorylation and Mitochondrial Mass Characterize CD66b+ Leukocytes from Patients with Sepsis

IntroductionSepsis leads to expansion of myeloid-derived suppressor cells (MDSC) and their subtypes. These normally transitory MDSCs suppress T cell activation and alter T cell cytokine production while simultaneously promulgating systemic low-grade inflammation. Immune metabolism can shape cell responses, regulate immune suppression, and enhance effector activity. Although MDSC metabolism has been extensively studied in cancer, the metabolic phenotype of this heterogeneous population in sepsis remains unclear. Our goal was to assess metabolic flux in blood MDSCs during and after sepsis and to stratify these patients clinical features and outcome with differences in metabolic flux that may guide treatment decisions. MethodsPeripheral blood mononuclear cells (PBMC) from healthy subjects and sepsis patients at 4 days, 2-3 weeks, and 6 months underwent CD66b+ or CD3+ enrichment, followed by assessment of metabolic flux, flow cytometry, mRNA sequencing, and chromatin accessibility. ResultsMitochondrial basal oxygen consumption rates (OCR) and maximal oxygen consumption rates (SRC, spare respiratory capacity) were decreased in MDSC from septic patients at 4 days after infection and persisted for up to 6 months after sepsis onset. Sepsis was not associated with differences in glycolysis. In contrast, oxidative metabolism in CD3+ T cells was similar between sepsis patients and healthy subjects. Reduced MDSC oxidative metabolism was linked to adverse clinical outcomes. The decline in oxygen consumption from MDSCs in septic patients was also associated with significant reductions in MDSC mitochondrial content. Transcriptomic analysis of CD66b+ cells isolated from PBMC of healthy participants and patients with sepsis at 4 days, 2-3 weeks, and 6 months revealed 19 differentially expressed genes and three long non-coding RNAs as potentially responsible for this decline in mitochondrial mass. Specifically, NR4A3, NR4A2, and TAMLIN/NR4A1 expression, all critical for mitochondrial biogenesis, were persistently decreased with reduced chromatin accessibility indicative of gene silencing. DiscussionAfter sepsis, blood CD66b+ cells present with reduced mitochondrial mass and oxidative metabolism that continue at least 6 months after sepsis. These changes in mitochondrial function result from a reduced content of these organelles. We have also identified gene silencing, reduced gene expression of key transcription factors that regulate mitochondrial biogenesis, as well as increased long non-coding RNA as potential drivers of this unique metabolic phenotype. These results highlight the potential benefit of targeting metabolism in sepsis to promote immune homeostasis and recovery.

immunology↗

bioRxiv2025

Age- and Sex- Driven Transcriptional and Metabolic Diversity in Myeloid-Derived Suppressor Cells After Mouse Sepsis

Sepsis induces profound immune dysregulation, often resulting in chronic critical illness characterized by persistent immunosuppression and poor outcomes. Myeloid-derived suppressor cells (MDSCs) are central mediators of this immunosuppressive phenotype, yet the influence of age and sex on their transcriptional and metabolic states remain poorly understood. Here, we employed single-cell RNA sequencing of splenic leukocytes from young (3-4 months) and older (18-24 months) adult male and female mice subjected to a clinically relevant murine sepsis model to define age- and sex-specific MDSC phenotypes. We identified significant differences regarding age and sex in MDSC expansion, transcriptome, canonical pathway activation, RNA velocity, mitochondrial metabolism, and predicted cell-cell communication after sepsis. Using drug2cell analysis of total leukocytes we also identified cohort-specific drug target profiles. These findings underscore the importance of age and sex in shaping sepsis-induced MDSC biology and suggest that personalized immunomodulatory strategies targeting MDSCs could improve sepsis outcomes.

immunology↗